Biological research is at the cusp of a technological revolution of the type that has repeatedly transformed research in recent decades. With the arrival of "next-generation" DNA sequencers, individual laboratories are able to ask questions that just five years ago required the resources of an entire institution. The transformational aspect of the new sequencers stems not only from their higher overall throughput in terms of bases per run, but also from their ability to permit digital DNA "counting" of DNA tags. Indeed, the newest of the next-gen sequencers count hundreds of millions of DNA tags per run, which in combination with up-stream sequence selection and preparation protocols, are poised to transform measurements of gene expression, regulation, and epigenetics. This Shared Instrumentation Grant requests such a next-generation sequencer-the Illumina GA IIx. Scientists at the UMN have imagined dozens of interesting applications for next-generation sequencing, but currently, they are hampered by our lack of a truly high-powered sequencer. They would like to use next-gen counting of transcripts to study control of cancer cells and to discover regulatory RNAs;they would like to carry out targeted re-sequencing of patient DNA to discover genetic variants responsible for differences in chemotherapy response;they would like to use sequence-based characterization of insertional mutagenesis to study carcinogenesis and to uncover mutations controlling the fundamental basis of meiosis. All of these questions are made possible once one can read, at a reasonable cost, and in a reasonable time frame, tens of billions of bases of DNA. Without this capability, however, interesting questions remain unanswered, and important hypotheses untested. The UMN's Biomedical Genomics Center (BMGC) currently provides genomic services at the UMN, and the BMGC proposes to put the GA IIx into shared use for the entire university. Our twelve scientists have the expertise, facilities, and other resources required to make best use of a GA IIx. Although we presently operate an early model of next-generation sequencer in the BMGC, in the critical metric of number of sequencing reads per run and cost per base, this now two-year old instrument is not a viable option. In short, the GAIIx will enable inquiries that are simply not achievable at present, and will therefore help UMN researchers move science closer to cures for important human diseases.